3-Halo-4-oxo-cyclohexane carboxylic acid esters

ABSTRACT

Tricyclic compounds of the formula   WHEREIN R1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxy carbonyl, nitro, amino, mono-lower alkylamino, dilower alkylamino, acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl, or difluoromethylsulfonyl; R2 is hydrogen, lower alkyl, amino-lower alkyl, mono-lower alkyl-amino-lower alkyl, or di-lower alkylamino-lower alkyl; n and r are independently 1 or 2; and X is oxygen or sulfur, prepared, inter alia, from the correspondingly substituted phenol or thiophenol and haloketocyclohexane or pentane carboxylic acid ester, are described. The end products are useful as anti-inflammatory and anti-rheumatic agents.

United States Patent [191 Berger et al.

[ Sept. 2, 1975 [73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Nov. 23, 1973 [21] Appl. No.: 418,328

Related US. Application Data [60] Division of Ser. No. 234,375, March13, 1972, which is a continuation-in-part of Ser. No. 128,570, March 26,1971, abandoned.

52 (1.5. CI. 260/468 J [51] Int. Cl. C07C 69/74 [58] Field of Search260/468 .1, 5 l4 J [56] References Cited UNITED STATES PATENTS 6/1974Wei 260/251 A OTHER PUBLICATIONS Fluorine Compound, pp.

Sheehan et al., J.O.C.S., 72, 2127, (1950).

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Samuel L. Welt;Bernard S. Leon; William G. lsgro [57] ABSTRACT Tricyclic compounds ofthe formula COOR I wherein R is hydrogen, halogen, lower alkyl, loweralkoxy, lower alkylthio, trifluoromethyl, cyano, carbamoyl, carboxy,lower alkoxy carbonyl, nitro, amino, mono-lower alkylamino, di-loweralkylamino, acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl, ordifluoromethylsulfonyl; R is hydrogen, lower alkyl, amino-lower alkyl,mono-lower alkyl-amino-lower alkyl, or di-lower alkylamino-lower alkyl;n and r are independently or 2; and X is oxygen or sulfur, prepared,inter alia, from the correspondingly substituted phenol or thiophenoland haloketocyclohexane or pentane carboxylic acid ester, are described.The end products are useful as anti-inflammatory and antirheumaticagents.

2 Claims, No Drawings BRIEF SUMMARY OF THE INVENTION The inventionrelates to racemic compounds of the formula (R COOR wherein Rindependently, is hydrogen, halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxycarbonyl, nitro, amino, mono-lower alkylamino, di-lower alkylamino,acyl, acylamido, sulfamoyl, di-lower alkylsulfamoyl, ordifluoromethylsulfonyl; R is hydrogen, lower alkyl, amino-lower alkyl,monolower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl; nand r are independently 1 or 2; and X is oxygen or sulfur, theirenantiomers, and when R is carboxy and/or R is hydrogen, salts thereofwith pharmaceutically acceptable bases, and when R is amino, mono loweralkylamino or di-lower alkylamino, and/or when R is amino-lower alkyl,mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl,addition salts thereof with pharmaceutically acceptable acids.

The compounds of formula I are useful as antiinflammatory andanti-rheumatic agents.

In other aspects, the invention relates to intermedi- VIa VIb

\ O-N IV 5 and R1- ll VII HAL

wherein R R R R r, n and X are as herein described.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term loweralkyl denotes a straight or branched chain hydrocarbon group containing1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertiary butyl, neopentyl, pentyl, heptyl, and the like. Theterm lower alkoxy denotes an alkyl ether group in which the alkyl groupis as described above, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentoxy and the like. The term lower alkylthiodenotes an alkylthio ether group in which the alkyl group is asdescribedabove, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, pentylthio, and the like. The term halogen"denotes all the halogens; that is, bromine, chlorine, fluorine andiodine; bromine and chlorine are preferred. The term acyl denotes analkanoyl group derived from an aliphatic carboxylic acid of 1 to 7carbon atoms, for example, formyl, acetyl, propionyl, and the like, andan aroyl group derived from an aromatic carboxylic acid, such as benzoyland the like. Exemplary of acylamido are acetamido, benzylamido and thelike. Exemplary of mono-lower alkylamino are methylamino, ethylamino andthe like. Exemplary of dilower alkylamino are dimethylamino,diethylamino and the like. Exemplary of amino-lower alkyl areaminomethyl, aminoethyl and the like. Exemplary of monoloweralkylaminoJower alkyl are rnethylaminomethyl, ethylaminoethyl and thelike. Exemplary of di-lower alkylamino-lower alkyl aredimethylaminomethyl, diethylaminoethyl and the like. Exemplary ofdi-lower alkylsulfamoyl are dimethylsulfamoyl, diethylsulfamoyl and thelike.

The invention relates to racemic compounds of the formula wherein R ishydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio,trifluoromethyl, cyano, carbamoyl, carboxy, lower alkoxycarbonyl, nitro,amino, mono-lower alkylamino, di-lower alkylamino, acyl, acylamido,sulfamoyl, di-lower alkylsulfamoyl or difluoromethylsulfonyl; R ishydrogen, lower alkyl, amino-lower alkyl, mono-lower alkylamino-loweralkyl or di-lower alkylamino-lower alkyl; n and r are indepcndently l or2; and X is oxygen, sulfur, their enantiomers, and when R, is carboxyand/or R is hydrogen, salts thereof with pharmaceutically acceptablebases, and when R is amino, mono-lower alkylamino or dilower alkylamino,and/or when R is amino-lower alkyl, mono-lower alkylamino-lower alkyl,or di-lower alkylamino-lower alkyl, addition salts thereof withpharmaceutically acceptable acids.

A preferred sub-genus of the invention comprises racemic compounds ofthe formula COORa R1) Ib COORQ herein R is as previously described, andR, is indemdently hydrogen, chlorine or cyano, provided that least oneof R, is hydrogen, their enantiomers and e respective salts thereof asherein described.

The most preferred compounds of the invention are:

8-chlorol ,2-dihydro-3(4H)-dibenz0furancarboxylic acid;

7-chlorol ,2-dihydro-3 4H )-dibenzofurancarboxylic acid; and

8-cyanol ,2-dihydro-3 4H )-dibenzofurancarboxylic acid.

Exemplary of the compounds of the invention correonding to formula Iwherein n is 2 and X is oxygen l,2-dihydro-3(4H),8-dibenzofurandicarboxylic acid;

8-acetyll ,2-dihydro-3( 4H )-dibenzofuran carboxylic acid;

8-aminol ,2-dihydro-3(4H )-dibenzofuran carboxylic acid;

8-aminol ,2-dihydro-3(4H )-dibenzofuran carboxylic acid ethyl ester;

7-aminol ,2-dihydro-3(4H)-dibenzofuran carboxylic acid ethyl ester;

7-amino-1 ,2-dihydro-3(4H)-dibenzofuran carboxylic acid;

8-chlorol ,2-dihydro-3(4H )-dibenzofuran carboxylic acid;

6-chlorol ,2-dihydro-3( 4H )-dibcnzofuran carboxylic acid;

9-chlorol ,2-dihydro-3(4H )-dibenzofuran carboxylic acid methyl ester;

9-chlorol ,2-dihydro-3(4H )-dibenzofuran carboxylic acid;

7-chloro-l,2-dihydro-3(4H)-dibenzofuran carboxylic acid; 5

l,2-dihydro-8-nitro-3(4H)-dibenzofuran carboxylic acid;

8-fluorol ,2-dihydro-3(4H)-dibenzofuran carboxylic acid; I

8-methyl-l ,2-dihydro-3(4H )-dibenzofuran carboxylic acid;

7-acetamido-l ,2-dihydro-3(4H)-dibenzofuran carboxylic acid ethyl ester;

7-acetamido-l ,2-dihydro-3( 4H )-dibenzofuran carboxylic acid; I

1 ,2-dihydro-7-meth0xy-3(4H )-dibenzofuran carboxylic acid;

7,9-dimethoxy-l ,2-dihydro-3(4H )-dibenzofuran carboxylic acid;

7,9-dichlorol ,2-dihydro-3( 4H)-dibenzofuran boxylic acid;

8-cyanol ,2-dihydro-3(4H)-dibenzofuran carboxylic acid;

8-cyano-3 ,4-dihydro-l (2H )-dibenzofuran carboxylic acid;

8-carbamoyl-l ,2-dihydro-3(4H )-dibenzofuran boxylic acid ethyl ester;8-cyano-3,4-dihydro-2( lH)-dibenzofuran carboxylic acid; and the like.

Exemplary of the compounds of the invention corresponding to formula Iwherein n is l and X is oxygen are:

2,3dihydrol H-cyclopenta[ b]benzofuran-2- carboxylic acid;

7-chloro-2,3-dihydrol H-cyclopenta[ b]benzofuran- Z-carboxylic acid;7-acetyl-2,3-dihydro- 1 l-l-cyclopenta[ b benzofuran- Z-carboxylic acid;

7-amino-2,3-dihydrol H-cyclopenta[blbenzofuran- 2-carboxylic acid;

7-amino-2,3-dihydro- 1 H-cyclopenta[ b benzofuran- 2-carboxylic acidethyl ester; 6-amino-2,3-dihydro-l H-cyclopenta[ b]benzofuran-2-carboxylic acid;

5-chloro-2,3-dihydrol H-cyclopenta[ b benzofuran- 2-carboxylic acid;

6-chlor0-2,3-dihydrol H-cyclopenta[b benzofuran- Z-carboxylic acid;

8-chloro-2,3-dihydro-l H-cycl0penta[ b]benzofuran- 2-carboxylic acid;

7-nitro-2,3-dihydrol H-cyclopenta[ b]benzofuran-2- carboxylic acid;

7-fluoro-2,3dihydrol H-cyclopenta[ b benzofuran- Z-carboxylic acid;

7-methyl-2,3-dihydrol H-cyclopenta[b]benzofuran- 2-carboxylic acid;

6-acetamido-2,3-dihydro l H- cycl0penta[b]benzofuran-Z-carboxylic acid;

6-acetamido-2,3-dihydrol H- cyclopentalb]benzofuran-2-carboxylic acidethyl ester; 6-methoxy-2,3-dihydro-l H-cyclopenta[b]benzofuran-2-carboxylic acid;

6,8-dimethoxy-2,3-dihydro l H- cyclopenta[b]benzofuran-2-carboxylicacid; 6,8-dichloro-2,3-dihydro-lH- cyclopenta[b]benzofuran-Zcarboxylicacid; 7-cyano-2,3-dihydrol H-cyclopenta[ b ]benzofuran- 2-carboxylicacid;

car-

car-

2 COORg O-N R Id herein I-IAL is halogen, for example, chlorine, fluone,bromine and iodine, preferred is fluorine; R is ydrogen or an electronwithdrawing group such as ni- 'o, trifluoromethyl, lower alkoxycarbonyl, cyano or :yl, provided that at least one of R is other thanhyrogen, and R and n are as described herein.

In Reaction Scheme I, the reaction of halobenzene of )rmula II with anoxime of formula III to yield an O- henyl oxime of formula IV isconveniently carried out 1 a polar solvent, such as dimethylsulfoxide,dimethyl- )rmamide, or hexamethylphosphoric triamide. The :actiontemperature is not critical. Preferably, the rection is carried out at atemperature in the range of '0m about room temperature to about thereflux temerature of the reaction mixture. The molar ratio of the:actants is not critical. Preferably, they are reacted in 1:] molarratio. I

The oxime of formula IV is converted to the comound of formula Idutilizing, for example, an acidic atalyst such as an organic, inorganicor Lewis acid, exmplary of which are hydrochloric acid, sulfuric acid,hosphoric acid, zinc chloride, copper chloride, boron 'ifluoride and thelike, and various combinations iereof. Conveniently, the reaction can becarried out i a polar solvent such as an alkanol, for example, iethanol,ethanol, propanol, and the like, water or a ydrocarbon such as benzene,toluene and the like. he reaction temperature is not critical.Preferably, the eaction is carried out at a temperature in the range ofem about room temperature to about the reflux temerature of the reactionmixture. The separation of the esired compound of formula Id from thereaction mix- .ire can be effected utilizing known techniques such 5,for example, filtration, crystallization, distillation nd the like.

A nitro group present in the compound of formula Id an be converted toan amino group utilizing known rocedures, for example, by catalyticreduction. An mino group can be converted to a diazonium salt utizingknown procedures, for example, by reaction with adium nitrite and amineral acid such as hydrohalic cid. A diazonium group can then bereplaced by a alogen, cyano, hydroxy, lower alkoxy or hydrogen utizingknown procedures, for example, by mixing a diaonium salt solution with,for example, a cuprous halie, cuprous cyanide, water, an alkanol or areducing gent, such as hypophosphorous acid, respectively, at oomtemperature or occasionally at elevated temperaures.

The preparation of compounds of formula I is also exemplified byReaction Scheme II.

Scheme II XE Hal V VI COORg VII (R1) (CH2) 00012 alkylated with thecorresponding haloketocycloalkane carboxylic acid ester of formula VI toyield a compound of formula V". The reaction is conveniently carried outin a non-polar solvent, for example, a hydrocarbon, such as benzene,toluene and the like, or a polar solvent, such as dimethylsulfoxide,dimethylformamide, hexamethylphosphoric triamide, and the like. Thereaction temperature is not critical. Preferably, the reaction iscarried out at a temperature in the range of from about room temperatureto about the reflux temperature of the reaction mixture. The molar ratioof the reactants is not critical. Preferably, they are reacted at a 1:1molar ratio.

A compound of formula VII is converted to a compound of formula Ie bythermal eyclization or by utilizing a cyclizing agent, such aspolyphosphoric acid, sulfuric acid, acetic acid, hydrochloric acid, andthe like. Preferably, the reaction is carried out at a temperature inthe range of from about 2() to about The reaction can be convenientlycarried out with or without a solvent. Exemplary of convenient solventsare acetic acid and the like.

The esters of formula Ie can be converted to the cor-' responding acid,i.e., the compounds of formula I wherein R is hydrogen, bysaponiflcation according to known procedures, for example, by reactionwith an alkali metal hydroxide such as sodium hydroxide, potassiumhydroxide and the like, and subsequent temperature with a mineral acid,for example, a hydrohalic acid, such as hydrochloric acid and the like.

The separation of the desired compound of formula Ie and itscorresponding acid from the reaction mixture can be effected utilizingknown techniques such as, for

example, filtration, crystallization, distillation and the like.

Furthermore, a salt of an acid of formula I, i.e., a salt of compoundsof formula I wherein R is hydrogen, can be converted toa compound offormula I wherein R is amino-lower alkyl, monolower alkylamino-loweralkyl or di-lower alkylaminolower alkyl by known procedures. Forexample, a salt of an acid of formula I is reacted with an amino-loweralkyl halide, mono-lower alkylamino-lower alkyl halide or di-loweralkylamino- VIII loweralkyl halide, exemplary of which are aminoethylchloride, methylamino-ethyl bromide, diethylaminomethyl chloride and thelike, to yield the desired end product. The temperature at which thereaction is effected is not critical; conveniently, the reaction iscarried out at a temperature in the range of from about room temperatureand about the reflux temperature of the reaction mixture. Conveniently,the reaction can be carried out in a polar solvent, such asdimethylformamide, dimethylsulfoxide or the like. The molar ratio ofreactants is not critical. Preferably, the reactants are utilized in al:l molar ratio.

The starting materials of formula II are known compounds or can beprepared in an analogous manner to known compounds. Exemplary of suchcompounds are:

4-fluoronitrobenzene; 4-f|uorocyanobenzene; 4-fluoroacetophenone; andthe like The starting materials of formula III are known compounds orcan be prepared in an analogous manner to known compounds. Exemplary ofsuch compounds are: 3-oxyiminocyclohexanecarboxylic acid methyl ester;4-oxyiminocyclohexanecarboxylic acid ethyl ester;2-oxyiminocyclohexanecarboxylic acid methyl ester;3-oxyiminocyclopentanecarboxylic acid propyl ester;2-oxyiminocyclopentanecarboxylic acid methyl ester;4-oxyiminocyclopentanecarboxylic acid methyl es ter; and the like. Theintermediates of formula IV are novel compounds. Exemplary of suchcompounds are:

3-(4'nitrophenoxyimino)cyclohexanecarboxylic acid and methyl esterthereof; 3( 2-nitrophenoxyimino)cyclohexanecarboxylic acid and methylester thereof; 3-( 4-cyanophenoxyimino )cyclohexanecarboxylic acid; 3-(2-trifluoromethylphenoxyimino )cyclohexanecarboxylic acid; 2-(4-nitrophenoxyimino )cyclopentanecarboxylic acid and methyl esterthereof; 2-( 4cyanophenoxyimino)cyclopentanecarboxylic acid and methylester thereof; and the like. The starting materials of formula V areknown com- 5 pounds or can be prepared in an analogous manner to knowncompounds. Exemplary of such compounds are:

4-chlorophenol; 5-chlorophenol; 4-nitrophenol;

p-cresol;

4-chlorothiophenol The starting materials of formula VI can be preparedas exemplified in Reaction Scheme III:

Scheme III n C00 2 COOR2 1 a 2 ii9e HAL acid and ethyl ester thereof;

3-( 4-chloro-phenylthio )-4-oxo-cyclohexanecarboxylic acid and ethylester thereof; 3 4-chlo ro-phenoxy )-4-oxo-cyclopentanecarboxylic acidand methyl ester thereof;

3-(4-chloro-phenylthio)-4-oxo-cyclopentane carboxylic acid and methylester thereof; and the like.

The compounds of formula I, when R is amino, mono-lower alkylamino ordi-lower alkylamino, and/or when R is amino-lower alkyl, mono-loweralkylamino lower alkyl or di-lower alkylamino-lower alkyl, form additionsalts with pharmaceutically acceptable organic or inorganic acids suchas hydrohalides, e.g., hydrochloride, hydrobromide, hydroiodide, othermineral acid salts such as sulfate, nitrate, phosphate and the like,alkyland mono-aryl sulfonates such as cthanesulfonate, toluenesulfonate,benzenesulfonate, or the like, other organic acid salts, such asacetate. tartrate, maleate, citrate, benzoate, salicylate, ascorhate andthe like.

The compounds of formula 1, when R is carboxy id/or R is lvxdrogen, formsalts with pharmaceutically :ceptable oases. Exemplary of such bases arealkali etal hydroxides, such as sodium hydroxide, potassium ldroxide,and the like; alkaline earth hydroxides, such calcium hydroxide, bariumhydroxide and the like; Idium alkoxides, such as sodium etholate,potassium holate and the like; organic bases such as piperidine,ethanolamine, N-methylglucamine and the like. Also cluded are thealuminum salts of the compounds of rmula I, when R is carboxy and/or Ris hydrogen. The compounds of formula 1, including the salts of .osecompounds of formula I which form salts with iarmaceutically acceptablebases and acids, possess iti-inflammatory activity and anti-rheumaticactivity, 1d are therefore useful as antiinflammatory agents 1danti-rheumatic agents. Their pharmacologically ieful activities aredemonstrated in warmblooded anials using standard procedures.

For example, the anti-inflammatory activity is demistrated in Albinorats of Hart Strain, weighing 25-155 gms. The test animals are given ml.of vehie, which contains the test compound per kg. of body eight. Theanimals are treated daily for 5 consecutive iys. Three hours after thefirst treatment, 0.05 ml. of 1 0.5 percent suspension of heat killeddessiccated 'ycobacterium bulyricum in U.S.P. olive oil, which has :ensteam sterilized for 30 minutes, is injected into the ght hind foot ofeach rat. The paw volume is mearred immediately after the injection ofthe adjuvant 1d again 96 hours later. The difference is recorded as)lume of edema. The paw volume is measured by imersion of the paw into acolumn of mercury to an ink ark exactly at the level of the lateralmalleolus. Per- :nt inhibition is calculated by dividing the averagentrol edema minus the average treatment edema by re average controledema times 100. The percent inhition is plotted against dose onsemi-logarithmic prob- )ility paper and the dose required to produce a30 :rcent reduction in edema is estimated therefrom and expressed as EDlilgar, A. G. and Hummel, D. .1.: Endocrine Bioassay Data, No. 1, p.August 1964 (Cancer Chemotherapy National Service Center, [.H.)

When 7-chloro-l ,2-dihydro-3(4l-l )-dibenzofuran trboxylic acid isutilized as the test substance at a dos- ;e of 11.5 mg. p.o., ananti-inflammatory activity is )served (ED-, 11.5).

The compounds of formula 1, their enantiomers and .lts as hereindescribed, have effects qualitatively sim- I! to those ofphenylbutazone, known for its therapeuuses and properties. Thus, thecompounds of this in- :ntion demonstrate a pattern of activityassociated ith anti-inflammatory agents of known efficacy and fety.

The compounds of formula 1, their enantiomers and Its as hereindescribed can be incorporated into stanll'd pharmaceutical dosage forms,for example, they e useful for oral or parenteral application with the.ual pharmaceutical adjuvant material, for example, ganic or inorganicinert carrier materials such as war, gelatin, lactose, starch, magnesiumstearate, talc, :getable oils, gums, polyalkylene-glycols and the like.1e pharmaceutical preparations can be employed in solid form, forexample, as tablets, troches, suppositoas, capsules, or in liquid form.for example, as solu- )ns, suspensions or emulsions. Pharmaceuticaladjumt materials can be added and include preservatives,

stabilizers, wetting or emulsifying agents, salts to change the osmoticpressure or to act as buffers. The pharmaceutical preparations can alsocontain other therapeutically active substances. 2

Since the compounds of the invention possess asymmetric carbon atoms,they are ordinarily obtained as racemic mixtures. The resolution of suchracemates into the optically active isomers can be carried out by knownprocedures. Some racemic mixtures can be precipitated as eutectics andcan thereafter be separated. Chemical resolution is, however, preferred.By this method, diastereomers are formed from the racemic mixture withan optically active resolving agent, for ex ample, an optically activebase, such as d-oz( l-naphthyl)ethylamine, which can be reacted with thecarboxyl group. The formed diastereomers are separated by selectivecrystallization and converted to the corresponding optical isomer. Thus,the invention covers the racemates of the compounds of formula I as wellas their optically active isomers.

The following examples further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of 3-(4-nitrophenoxyimino)cyclohexanecarboxylicacid A mixture of 12.1 g. of potassium t-butoxide and 8.5 g. of3-oxyiminocyclohexanecarboxylic acid in ml. of dimethylsulfoxide wastreated with 5.73 ml. of 4- fluoronitrobenzene, stirred vigorously atroom temperature for 2 hours, diluted with 450 ml. of saturated sodiumchloride solution and acidified with acetic acid.

The precipitate was removed by filtration, washed successively withwater and pentane, and dried to give 14.25 g. of 3-(4-nitrophenoxyiminocyclohexanecarboxylic acid as light yellow crystals, m.p. l4615 1 dec.This material can be used for the next step without purification.Recrystallized from methylene chloride ether,3-(4-nitrophenoxyimino)cyclohexanecarboxylic acid has a melting point ofl58.5l59 dec.

Analysis calcd. for C H N O (278.26):

Found C, 56.42; H, 5.08; N, 10.37.

EXAMPLE 2 Preparation of l ,2-dihydr0-8-nitro-3(4H)-dibenzofurancarboxylic acid I A solution of 23.4 g. of3-(4-nitrophenoxyimino)cy clohexanecarboxylic acid in 250 ml. of aceticacid containing 29 g. of hydrogen chloride was stirred at 90 for 17hours. Thereafter, the reaction mixture was cooled to 30 and filtered.The solid residue was washed successively with acetic acid, hexane andwater, and dried to give 8.5 g. of 1,2-dihydro-8-nitro-3(4H)-dibenzofuranacarboxylic acid as tan crystals, m.p. 229231.5. Thismaterial can be used for the next step without purification.Recrystallized from acetoneether, 1 ,2-dihydro-8-nitro-3( 4H)-diben7.ofurancarboxylic acid has a melting point of 226230.

Analysis Calcd. for C H NO (261.24

c, 59.77; H, 4.24; N, 5.36.

Found: C, 59.57; H, 4.22; N, 5.5l.

EXAMPLE 3 Preparation of 8'amino-l ,2-dihydro-3( 4H)-diben7.ofurancarboxylic acid A solution of 4.83 g. of1,2-dihydro-8-nitro3(4H)- dibenzofurancarboxylic acid in 150 ml. ofacetic acid was reduced in the Brown hydrogenator with l g. of 10percent palladium-on-charcoal catalyst. The catalyst was removed byfiltration. The filtrate was evaporated,

and the residue was crystallized from acetonitrile-ether to give 3.4 g.of 8-amino-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid as browncrystals, m.p. 235235.5 dec. This material may be used in succeedingsteps without further purification. Crystallized from acetonitrileetheras light brown crystals, 8-amino-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid has a melting point of23123l.5 dec.

Analysis Calcd. for C H NO (231.25):

Found: C, 67.52; H, 5.67; N, 6.06.

Found: C, 67.35; H, 5.68; N, 6.05.

EXAMPLE 4 Preparation of 8-amino-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester hydrochloride A solution of lg. of S-amino-l ,2-dihydro-3(4H)- dibenzofurancarboxylic acid in 100 ml.of ethanol saturated with hydrogen chloride was heated at refluxtemperature for two hours and then evaporated to dryness. The residuewas crystallized from ethanol-ether to give 986 mg. (89 percent) of8-amino-1,2-dihydro-3(4H)- dibenzofurancarboxylic acid ethyl esterhydrochloride as white crystals, m.p. 250251dec. Crystallized fromethanol-ether as white crystals, 8-amino-1,2-dihydro-3(4H)dibenzofurancarboxylic acid ethyl ester hydrochloride has a meltingpoint of 251252 dec.

Analysis Calcd. for C H NO .HCl (295.77):

C, 60.91; H, 6.13; N, 4.74.

Found: C, 61.11; H. 6.28; N, 4.91.

EXAMPLE Preparation of 3-bromo-4-ketocyclohexanecarboxylic acid ethylester A solution of 40 g. of 4-ketocyclohexanecarboxylic acid ethylester in 650 ml. of ether was stirred at during the dropwise addition of12.05 ml. of bromide. The resultant colorless solution was washedsuccessively with water, saturated sodium bicarbonate solution, andagain with water. The organic layer was dried over sodium sulfate andevaporated to give 59 g. of 3- bromo-4-ketocyclohexanecarhoxylic acidethyl ester as a colorless oil. This material may be used for the nextstep without further purification, and may be kept for 2 to 3 days undernitrogen, without significant decom position. For analysis, a sample wasdistilled, b.p. 95/().()01 mm.

Analysis Calcd. for C H BrQ, (249.1 1

Found: 43.24; H, 5.22.

EXAMPLE 6 Preparation of8-chloro-1,2-dihydro-3(4-H)-dibenzofurancarboxylic acid Method A Asuspension of 2 g. of 8-amino-1,2dihydro-3(4H)- dibenzofurancarboxylicacid in 12 ml. of water and 20 ml. of concentrated hydrochloric acid,stirred at 0, was treated dropwise with a cold solution of 716 mg. ofsodium nitrite in 20 ml. of water. The diazotization solu' tion wasstirred at 0 for 30 minutes and then was added gradually to a coldsolution of 1.3 g. of cuprous chloride in 18 ml. of concentratedhydrochloric acid. The mixture was stirred for 2.5 hours at roomtemperature, diluted with water, and filtered to give 1.78 g. of 8-chlorol ,2-dihydro-3(4H)-dibenzofurancarb0xylic acid as tan crystals,m.p. l94198.5. A pure sample of 8-chlorol,2-dihydro-3(4H)-dibenzofurancarboxylic acid as white crystals, m.p.198201, was obtained in about 50 percent yield by sublimation at190/0.05

Analysis Calcd. for C H ClO (250.68):

C, 62.29; H, 4.42; N, 14.14.

Found: C, 62.24; H, 4.35; N, 13.76. Method B A suspension of sodium4-chlorophenoxide, prepared from 1 1.6 g. of 4-chlorophenol and 4.86 g.of sodium methoxide, and 22.5 g. of 3-bromo-4-ketocyclohexanecarboxylicacid ethyl ester in 300 ml. of benzene was stirred for 64 hours at roomtemperature. The mixture was then washed successively with 1N sodiumhydroxide and water. The organic layer was dried over sodium sulfate andevaporated to give 18.30 g. of3(pchlorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester as ayellow oil. A mixture of 18.25 g. of this material and 180 g. ofpolyphosphoric acid was stirred for 10 minutes at room temperature andthen quenched with ice and water. The resulting solution was extractedwith ether. The organic layer was washed successively with 1N sodiumhydroxide and water, dried and evaporated to give 15.6 g. of viscousoil, which, after distillation, gave 10.2 g. of 8-chloro-l,2dihydro-3(4H)- dibenzofurancarboxylic acid ethyl ester as alight yellowoil, b.p. l-l85/1 mm. A solution of 10.2 g. of 8-chloro-1,2-dihydro-3(4H )dibenzofurancarboxylic acid ethyl ester, ml. of 1Nsodium hydroxide and 300 ml. of ethanol was heated at reflux temperaturefor 1.5 hours and then concentrated at reduced pressure. Afterextraction with methylene chloride, the aqueous layer was treated withcharcoal and filtered. The filtrate was cooled in ice water andacidified with 25 ml. of concentrated hydrochloric acid. The precipitatewas filtered, washed with water, and dried to give 7 g. of crystals,m.p. 199.5201, which were identical with the 8-chlorol ,2-dihydro-3 4H)-dibenzofurancarboxylic acid obtained by Method A.

EXAMPLE 7 Preparation of 8-flu0ro- 1 ,2-dihydro-3( 4H)-dibenzofurancarboxylic acid A suspension of sodium p-fluorophenoxide,prepared from 1 1.2 g. of p-fluorophenol, 5.4 g. sodium methoxide and26.8 g. of 3-bromo-4-ketocyclohexanecarboxy-' lic acid ethyl ester in200 ml. of benzene was stirred for 16 hours at room temperature. Thereaction mixture was washed with water, 1N sodium hydroxide, andsaturated sodium chloride solution, and was dried over sodium sulfate.Evaporation of the solvent gas 22.1 g. of 3-( p-fluorophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester.

A mixture of 17.1 g; of this material'and 150 g. of )olyphosphoric acidwas stirred for 10 minutes at room emperature, then quenched with icewater and exracted three times with ether. The organic portion wasvashed with sodium bicarbonate and saturated sodium :hloride solutions,dried, and evaporated to dryness to ;ive 15.8 g. of an oil which wasdistilled in a Kugelrohr wen to give 7.75 g. of8-fluoro-1,2-dihydro-3(4H)- liben zofurancarboxylic acid ethyl ester asa colorless )il. This material was heated at reflux temperature for hourin a mixture of 75 ml. of ethanol and 50 ml. of

N sodium hydroxide. The ethanol was evaporated lnder reduced pressure.After the addition of 50 ml. of vater, the reaction mixture was treatedwith charcoal ind neutralized with 25 ml. of 2N hydrochloric acid. Fhesolids which formed were removed by filtration md crystallized fromacetone-water to give 3.65 g. of l-fluoro- 1,2-dihydro-3(4H)-dibenzofurancarboxylic \cid as white crystals, m.p.208210.

Analysis Calcd. for C H FO (234.23):

Found: C, 66.68; H, 4.93.

EXAMPLE 8 Preparation of 8-methyl-l ,2-dihydro-3 4H)-dibenzofurancarboxylic acid A suspension of sodium p-cresolate,prepared from 1.24 g. of p-cresol and 1.62 g. of sodium methoxide, md7.45 g. of 3-bromo-4-ketocyclohexanecarboxylic lCld ethyl ester in 100ml. of dry benzene was stirred 'or 64 hours at room temperature. Themixture was hen washed successively with water, 1N sodium hylroxide andwater. The aqueous layers were extracted 1 times with benzene. Theorganic layers were dried iver sodium sulfate and evaporated to give 6.1l g. of l-(p-methylphenoxy)-4-oxocyclohexanecarboxylic [Cid ethyl esteras a yellow oil.

A solution of 1.9 g. of the above material in 5 ml. of :ther wascombined with 19 g. of polyphosphoric acid md stirred for 20 minutes atroom temperature under nitrogen. The reaction was quenched by additionof ice vater, and the resulting mixture was stirred until a soluion wasobtained. This solution was extracted three imes with ether. The organiclayers were washed with vater, saturated sodium bicarbonate solution,water, ind dried over sodium sulfate. Evaporation of the solent gave1.62 g. of a yellow oil which was distilled lnder vacuum to give 1.2 g.of 8-methyl-l,2-dihydro- 5(41-1)-dibenzofurancarboxylic acid ethylester. A soluion of this material 1.2 g.) in 9 ml. of 1N sodiumhylroxide, and 9 ml. of ethanol was heated at relux temerature for 1hours under a nitrogen atmosphere. The :thanol was removed under vaccum.The residue was lissolved in water, treated with charcoal, and filtered.lhe filtrate was cooled in an ice water bath and acidiied with 2Nhydrochloric acid. The precipitate which 'ormed was filtered andcrystallized from ether- )entane to give 250 mg. of S-methyl-LZ-dihydro-1(4H)-dibenzofurancarboxylic acid, m.p. 199-2()1.

Analysis Calcd. for C H Q, (230.26):

Found: C, 72.65; H, 6.31.

EXAMPLE 9 Preparation of6-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid To a solution of6.43 g. of freshly distilled 2- chlorophenol in 100 ml. of methanol wasadded 2.7 g.

of sodium methoxide, and the resulting solution was evaporated todryness under reduced pressure to give 7.5 g. of sodium2-chlorophenoxide. A suspension of the above sodium salt and of 12.5 g.of 3-bromo 4- ketocyclohexanecarboxylic acid ethyl ester in 150 ml. ofbenzene was stirred overnight at room temperature.--

The reaction mixture was washed with ml. portions of water, two 50 ml.portions of 1N sodium hydroxide, and three 50 ml. portions of brine. Theorganic layers were dried over sodium sulfate and evaporated to drynessto give 1 1.85 g. of 3-(o-chlorophenoxy)-4-oxocyclohexanecarboxylic acidethyl ester as a dark yellow oil. 1

A mixture of 1 g. of 3-(o-chlorophenoxy)-4-oxocyclohexanecarboxylic acidethyl ester and 10 g. of polyphosphoric acid was stirred for 1 hour at75. After the addition of 25 ml. of ice water, the reaction mixture wasextracted three times with 100 ml. portions of ether. The organic layerswere washed with water, 1N sodium bicarbonate and with brine. The etherextracts were dried over sodium sulfate, evaporated to dryness, and theresidue (955 mg.) was distilled in a Kugelrohr oven at 200/0.2 mm. togive 475 mg. of 6-chloro-1,2- dihydro-3(4H -dibenzofurancarboxylic acidethyl ester as a yellow oil. A solution of this material in 10 ml. ofethanol and 5 ml. of 2N sodium hydroxide was heated at refluxtemperature for 1 hour. After removal of the ethanol, the resultingcloudy solution was treated with charcoal, filtered and treated with 5ml. of 2N HCl. The solids which formed were removed by filtration andcrystallized from acetonitrile to give 250 mg. of 6- chlorol,2-dihydro-3(4H )-dibenzofurancarboxylic acid as white crystals, m.p.188l92C. Recrystallization from acetone-water gave 230 mg. of 6-chloro-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. 190'l 93C.

Analysis Calcd. for C H ClO (250.68):

Found: C, 61.99; H, 4.29.

EXAMPLE l0 9-chloro-1 ,2-dihydro-3( 4H )-dibenzofurancarboxylic acidSodium 3-chlorophenoxide, prepared from 1 1.6 g. of 3-chlorophenol and4.86 g. of sodium methoxide, in 300 ml. of dry benzene was stirred for10 hours at room temperature with 21g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester. The suspension waswashed twice with ml. portions of water, once with 100 ml. of 1N sodiumhydroxide, and thrice with 100 ml. portions of water. The aqueous layerswere extracted twice with ml. portions of benzene. The combined organiclayers were dried with sodium sulfate and evaporated to give 20.4 g. of3-(3- chlorophenoxy )-4-oxocyclohexanecarboxylic acid ethyl ester. Amixture of 5.63 g. of this material and 85 g. of polyphosphoric acid wasstirred at 75 for 1 hour,

decomposed with ice and water, and extracted 3 times with 250 ml.portions of ether. The organic layers were washed twice with 200 ml.portions of water, once with 150 ml. of saturated sodium bicarbonatesolution, and three times with 200 ml. portions of water, and were thendried with sodium sulfate and evaporated to give 4.5 g. of brown oil.Distillation of l90/0.2 mm. gave 3.5 g. of a mixture of the isomericesters 7-chloro-l ,2- dihydro-3-(4H)dibenzofurancarboxylic acid ethylester and 9-chloro-l ,2dihydro-3(4H )-dibenzofurancarboxylic acid ethylester. A solution of 3.48 g. of this material in 70 ml. of 1N sodiumhydroxide and 140 ml. of ethanol was stirred at reflux temperature for 1hour and then evaporated. The residue was dissolved in water, stirredwith charcoal and filtered. The filtrate was acidified with concentratedhydrochloric acid, and the resulting precipitate was collected to give2.72 g. of an isomeric mixture of 7-chloro-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid and 9-chlor0-l ,Z-dihydro-3(4H)-dibenzofurancarboxylic acid as a gray solid, mp. l48-l63.Recrystallization from ether-pentane gave 1.51 g. of the isomericmixture 7-chloro-l,2 dihydro-3(4H)dibenzofurancarboxylic acid and 9-chloro-l ,2-dihydro-3( 4H )dibenzofurancarboxylic acid as yellowishcrystals, m.p. l52-l 80. Crystallized from methylenechloride-ether-pentane; 7-chloro-l;2-dihydro-3(4H)-dibenzofurancarboxylic acid and 9- chloro-l ,2-dihydro-3(4H )-dibenzofurancarboxylic acid as white crystals had a melting pointof l67l 85.

Analysis calc. for C H ClO (250.68):

Found: C, 62.38; H, 4.68.

EXAMPLE 1 1 Preparation of 9-chlorol ,2-dihydro-3( 4H)-dibenzofurancarboxylic acid methyl ester A solution of 5.65 g. of themixture of isomers 7- chloro-l ,2-dihydro-3(4H )-dibenzofurancarboxylicacid and 9-chlorol ,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p.l3ll55, in 100 ml of methanol saturated with hydrogen chloride wasstirred at reflux temperature for 1 hour. Evaporation of the solvent andcrystallization of the residue from ether-pentane gave 884 mg. of9-chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid methyl ester asyellowish crystals, m.p. 99-102. A sample for analysis was sublimed at9()-l00/0. l 2 mm. as white crystals, m.p. ll-l02.5.

Analysis Calcd. for C H ClQ, (264.71

Found: C. 63.35; H. 4.82

EXAMPLE 12 Preparation of 9-chlorol ,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of 840 mg. of9-chloro-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid methyl ester in15 ml. of 1N sodium hydroxide and 30 ml. of ethanol was stirred atreflux temperature for 1 hour and then evaporated. The residue wasdissolved in water and extracted three times with 75 ml. portions ofmethylene chloride. The aqueous layer was stirred with charcoal, andfil' tered, and the filtrate was acidified with concentratedhydrochloric acid. The precipitate was filtered, dried and crystallizedfrom tetrahydrofuran-ether-pentane to give 452 mg. of9-chloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid as whitecrystals, m.p. l89l90.

Analysis Calcd. For C H ClO (250.68): C, 62.29; H, 4.42. Found: C,62.51; H, 4.51.

EXAMPLE 1 3 Preparation of 7-acetamido-l ,2-dihydro-3( 4H)-dibenzofurancarboxylie acid ethyl ester A suspension of 15.] g. of3-acetamidophenol and 13.8 g. of potassium carbonate in 60 ml. ofdimethylformamide was heated with stirring at for 10 minutes. A solutionof 24.9 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 25ml. of dimethylformamide was added dropwise to the above suspension.After 15 minutes, the reaction mixture was concentrated, diluted withwater and extracted 3 times with ether. The ether extracts were washedwith lN sodium hydroxide, water, and dried over sodium sulfate.Evaporation of the solvent gave 18.0 g. of3-(macetamidophenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester. Amixture of 16 g. of this material and 160 g. of polyphosphoric acid wasstirred for 30 minutes at room temperature. An excess of ice water wasadded. The precipitate which formed was filtered, dried, dis solved inmethylene chloride, and filtered through a column of alumina (activitygrade II). The methylene chloride eluates were evaporated to give 1 l .lg. of an oil which was crystallized from methylene chlorideether-pentaneto give 4.5 g. of 7-acetamido-l ,2- dihydro-3(4H)-dibenzofurancarboxylicacid ethyl ester, m.p. ll5-l 16.

Analysis Calcd. for C, H NO (301.33):

C, 67.76; H, 6.36; N, 4.65.

Found: C, 68.07; H, 6.35; N, 4.62.

EXAMPLE 14 Preparation of 7amino-l ,2-dihydro-3( 4H)dibenzofurancarboxylic acid ethyl ester hydrochloride A solution of 2.9g. of 7-acetamido-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid ethylester in etha nolic hydrogen chloride was heated at reflux temperaturefor 2 hours. The solvent was removed under vacuum. Crystallization ofthe residue from ethanol'ether gave 2.2 g. of 7-amino-l ,2dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester hydrochloride,m.p. 226-228.

Analysis Calcd. for C H, NO .HCl(295.75): C, 60.9]; H, 6.13; N, 4.74.

Found: C, 60.62; H, 6.24; N, 4.64.

EXAMPLE 15 Preparation of 7-chloro-l ,2-dihydro-3( 4H)-dibenzofurancarboxylic acid A solution of mg. of sodium nitrite in 2ml. of water was added dropwise, under nitrogen, to a cooled solution of590 mg. of 7-amino-l ,2-dihydro-3(4H dibenzofurancarboxylic acid ethylester hydrochloride in 5 ml. of acetic acid2water l:l The resultingsolution was added dropwise, under nitrogen, to a suspension of 238 mg.of cuprous chloride in 2 ml. of cone, hydrochloride acid at 5. Thereaction mixture was rred at room temperature for 30 minutes, thenexrcted three times with ether. The ether layers were rshed 1Nhydrochloric acid, 1N sodium hydroxide, rter, and dried over sodiumsulfate. Evaporation of e solvent gave 510 mg. of an oil, which wasdistilled a Kugelrohr oven, to give 444 mg. of 7-ch1oro-l,2-hydro-3(4H)dibenzofurancarboxylic acid ethyl ester a yellow oil. Asolution of 420 mg. of this material, ml. of 1N sodium hydroxide, and 10ml. of ethanol is heated at relux temperature for 1 hour. The solvent 18removed under vacuum. The remaining residue is dissolved in water. Theaqueous solution was exrcted two times with ether, cooled and acidifiedwith J hydrochloric acid. The precipitate which formed 18 filtered andcrystallized from acetone-water to give mg. of a-solid, m.p. 189191.This material was crystallized from acetone-ether to give 1 10 mg. of 7-loro-l ,2-dihydro-3 4H )-dibenzofurancarboxylic id, m.p. l94196.

Analysis Calcd. for C l-l ClO (250.68):

Found: C, 62.33; H, 4.22.

EXAMPLE 16 Preparation of acetamido-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid A solution of 1.2 g. of7-acetamido-1,2-dihydro- 4H)-dibenzofurancarboxylic acid ethyl ester, 10ml.

1N sodium hydroxide, and 10 ml. of ethanol was ated at relux temperaturefor 1 hour. The solvent was moved under vacuum. The residue wasdissolved in iter and acidified with 2N hydrochloric acid. The ecipitatewas filtered and crystallized from acetoneiter to give 75 mg. of7-acetamido-l,2-dihydro- 4H)-dibenzofurancarboxylic acid, m.p. 229230.Analysis Calcd. for C, H, =,NO (273.28): C, 65.92; H, 5.53; N, 5.13.Found: C, 65.71; H, 5.26; N, 4.98.

EXAMPLE 1 7 Preparation of -amino-l ,2-dihydro-3 4H)-dibenzofurancarboxylic acid hydrochloride A solution of 100 mg. of7-amino-l ,2-dihydro- 4H )-dibenzofurancarboxylic acid ethyl esterhydroloride, 3 ml. of 1N sodium hydroxide and 10 ml. of ianol was heatedat reflux temperature for 1 hour. 1e solvent was removed under vacuum.The residue 18 dissolved in water, cooled, and acidified with 1Ndrochloric acid. The solid was filtered and crystaled frommethanol/ether to give 45 mg. of 7-amino-Z-dihydro-3(4H)-dibenzofurancarboxylic acid hyachloride, m.p. 290300.

Analysis Calcd. for C ;H NO .HC1 (267.70):

I, 58.33; H, 5.27; N, 5.23; C], 13.24.

?ound: C, 58.32; H, 5.48; N, 5.14; C], 13.37.

EXAMPLE 1 8 Preparation of nethoxyl ,2-dihydro-3(4H)-dibenzofurancarboxylic acid A suspension of 6.2 g. of freshlydistilled 3- :thoxyphenol and 6.9 g. of potassium carbonate in 20 ofdimethylformamide was heated at 100 for nutes. To the stirred suspensionwas added dropwise 12.5 g. of 3-bromo-4-ketocyclohexanecarboxylic acidethyl ester in 5 ml. of dimethylformamide, and the resulting mixture wasstirred at 100 for 30 minutes. After cooling, 150 ml. of water wasadded, and the reaction mixture was extracted with three 150 ml.portions of ether. The ether layers were washed with 1N sodium hydroxideand water, dried over sodium sulfate, and treated with charcoal.Evaporation of the solvent gave 8.5 g. of3-(m-methoxyphenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester as ayellow oil. A mixture of this material and g. of polyphosphoric acid wasstirred for 15 minutes at room temperature, and added to 150 ml. of icewater. Thereafter, the mixture was extracted with three 150 m1. portionsof ether. The ether extracts were washed with saturated aqueous sodiumbicarbonate and brine, and dried over sodium sulfatev Evaporation of thesolvent gave 7 g. of 7-methoxy-1,2- dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester as a dark oil, which wasdissolved in ml. of ethanol and 50 ml. of 2N sodium hydroxide. Theresulting solution was heated at reflux temperature for 1 hour. Theethanol was removed under reduced pressure. After the addition of ml. ofwater, the reactionmixture was extracted with ether. The aqueous layerwas treated with charcoal, cooled in an ice water bath, and neutralizedwith 50 ml. of 2N hydrochloric acid. The solids which formed wereremoved by filtration and were crystallized from acetone-water to give3.8 g. of crystals, m.p. l 80. Recrystallization from acetonitrile-watergave 7-methoxy-1 ,2-dihydro-3(4H dibenzofurancarboxylic acid as whitecrystals, m.p. l8l183.

Analysis Calcd. for C I-[ 0 (246.25):

Found: C, 68.45; H, 5.91.

EXAMPLE 19 Preparation of 7,9-dimethoxyl ,2-dihydro-3 4H)-dibenzofurancarboxylic acid A suspension of 3.08 g. of3,5-dimethoxyphenol, 2.76 g. of potassium carbonate and 4.98 g. of3-bromo-4- ketocyclohexanecarboxylic acid ethyl ester in 30 ml. ofdimethylformamide was stirred at 100 for 2 hours. Thereafter, 150 ml. ofice water was added, and the resulting solution was extracted threetimes with 100 ml. portions of ether. The ether layers were washed with1N sodium hydroxide and with water, dried over sodium sulfate, andevaporated to dryness. The residue (3.3 g.)3(3,S-dimethoxyphenoxy)-4-oxocyclohexanecarboxylic acid ethyl ester wasstirred at room temperature for 15 minutes with 33 g. of polyphosphoricacid. After the addition of 150 ml. of water, the reaction mixture wasextracted 3 times with 100 ml. portions of ether. The ether layers werewashed with sodium bicarbonate and saturated sodium chloride solutions,dried over sodium sulfate, and evaporated to dryness to give 2.7 g. of7,9-dimethoxy-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid ethylester. This material was dissolved in 50ml. of ethanol and 25 ml. of 2Nsodium hydroxide, and the resulting solution was heated at refluxtemperature for 1 hour. The reaction mixture was cooled, and the ethanolwas removed under reduced pressure. The residue which formed was dilutedwith water, treated with charcoal, cooled in an ice bath and neutralizedwith 25 ml. of 2N hydrochloric acid. The solids which formed wereremoved by filtration and crystallized from acetone-water to give 1 g.of 7 ,9-dimethoxy- 1 ,2-dihydro-3( 4H )-diben2ofurancarboxylic acid,m.p. 194l96.

Analysis Calcd. for C,,-,H ,O (276.29):

Found: C, 65.13; H, 5.95.

EXAMPLE 20 Preparation of 7,9-dichloro-l ,2-dihydro-3( 4H)-dibenzofurancarboxylic acid A solution of 3.12 g. of3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 5 ml. ofdimethylformamide was added dropwise to a suspension of 2.04 g. of3,5-dich1orophenol and 0.865 g. of potassium carbonate in 25 ml. ofdimethylformamide. The resulting mixture was heated for 2 hours at 100.Thereafter, it was cooled to room temperature, diluted with water, andextracted three times with ether. The organic layers were washed withwater, saturated sodium bicarbonate solution, and water, dried oversodium sulfate, and evaporated to give 3.7 g. of3-(3,5-dichlorophenoxy)- 4-oxocyclohexanecarboxylic acid ethyl ester.This material was combined with 38 g. of polyphosphoric acid and heatedfor 1 hour at 70. The reaction was quenched by addition of ice water,and the resulting solution was extracted 3 times with ether. The organiclayers were washed with water, saturated sodium bicarbonate solution,and water, dried over sodium sulfate, and evaporated to give 2.7 g. of7,9-dichloro-l ,2- dihydro-3(4 H)-dibenzofurancarboxylic acid ethylester. A solution of 2.7 g. of 7,9-dichloro-1,2-dihydr0-3(4H)-dibenzofurancarboxylic acid ethyl ester, 25 ml. of 1N sodiumhydroxide, and 25 m1. of ethanol was heated at reflux temperature for 1hour. The ethanol was removed under vacuum. The residue was dissolved inwater, extracted 2 times with ether, cooled in an ice water bath, andacidified with 2N hydrochloric acid. The precipitate which formed wasfiltered and dried under vacuum to give 2.0 g. of a solid, m.p. l90-200.Crystallization from acetone-ether gave 1.06 g. of 7,9- dichloro-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid, m.p. 223-225.

Analysis Calcd. for C -,H, ,Cl- O=, (285.13):

Found: C, 54.65; H, 3.86.

EXAMPLE 2l PREPARATlON OF 3-( 4-cyanophenoxyimino )cyclohexanecarboxylicacid To a solution of 2.26 g. of potassium t-butoxide in 18 ml. ofdimethylsulfoxide, stirred vigorously at room temperature. was added1.57 g. of 3-oxyiminocyclohexanecarboxylic acid. After minutes, themixture was treated with 1.21 g. of p-fluorobenzonitrile, stirred for 2hours, diluted with 150 ml. of saturated sodium chloride solution, andacidified with acetic acid. The solid which formed was removed byfiltration, dried and crystallized from tetrahydrofuran-etherpentane togive 1.6 g. of 3-(4-cyanophenoxyimino)cyclohexanecarboxylic acid aswhite crystals, m.p. 153-l54.

Analysis Calcd. for C H N Q, (258.28):

C. 65.10; H, 5.46; N, 10.85.

Found: C. 65.01: H. 5.48: N, 10.87.

EXAMPLE 22 PREPARATION OF 8-cyanol ,2-dihydro-3( 4H)-dibenzofuranearboxylic acid A solution of 258 mg. of 3-(4-cyanophenoxyimino)cyclohexanecarboxylic acid in 25 ml. of acetic acidsaturated with hydrogen chloride was heated on a steambath overnight,and then evaporated to dryness. The residue was digested on thesteambath with 3 ml. of acetic acid. Thereafter, the mixture cooled to25, and the solid which formed was removed by filtration to give 99 mg.of 8-cyano-l,2-dihydro- 3(4H)-dibenzofurancarboxylic acid as whitecrystals, m.p. 25 3-25 5. Crystallized fromtetrahydrofuranether-pentane, as white crystals, 8-cyano-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid had a melting point of 249250.

Analysis Calcd. for C H NQ, (241.26): C, 69.70; H, 4.59; N, 5.80. Found:C, 69,69; H, 4.60; N, 5.77.

EXAMPLE 23 PREPARATION OF 8-cyano-3 ,4-dihydro- 1 2H)-dibenzofurancarboxylic acid Fractional crystallization of 15 g. of themother liquors obtained from the preparation of 8-cyano-l,2-dihydro-3(4H)-dibenzofurancarboxylic acid gave 4.5 g. ofa tan solid,m.p. 185-1 Two g. of this material was filtered through a column of 8 g.of Florisil; The column was eluted successively with benzene, methylenechloride, ether and ethyl acetate. The methylene chloride and the ethereluates were combined and crystallized twice from methylenechloride-ether-pentane to give 340 mg. of8-cyano-3,4-dihydro-l(2H)-dibenzofurancarboxylic acid, m.p. 195l96.

Analysis Calcd. for C H NO (241.26):

C, 69.70; H, 4.59; N, 5.80.

Found: C, 69.75; H, 4.73; N, 5.81.

EXAMPLE 24 Preparation of S-carbamoyl-l ,2-dihydro-3 4H)-dibenzofurancarboxylic acid ethyl ester 1 A suspension of 1 g. of8-cyano-l,2-dihydro-3(4H)- dibenzofurancarboxylic acid in ml. of ethanolwas stirred in an ice water bath and was saturated with hydrogenchloride. The mixture was refrigerated overnight and then heated toreflux temperature for 4 hours with the introduction of hydrogenchloride. The solution was evaporated to dryness, and the residue waspartitioned between methylene chloride and dilute sodium hydroxide. Theorganic layer was washed with water, dried and evaporated to give 1.1 g.of solid, which was crystallized from methylene chloride-ether to give283 mg. of 8-carbamoyl-l ,2-dihydro-3(4H)- dibenzofurancarboxylic acidethyl ester as white crystals, m.p. 206.5207.5. Crystallized twice frommethylene chloride-ether as white crystals, 8carbamoyl1,2-dihydro-3(4H)-dibenzofurancarboxylic acid ethyl ester had a meltingpoint of 2()7.5208.

Analysis Calcd. for C H NO (287.33):

C. 66.88; H. 5.97; N, 4.87.

Found: C, 67.01; H, 5.69; N, 4.85.

EXAMPLE 25 Preparation of 1 ,2-dihydro-3(4H ),8-dibenzofurandicarboxylicacid A mixture of 250 mg. of 8-cyano- 1 ,2-dihydro-3(4H)-:libenzofurancarboxylic acid and 3 ml. of a 30 percent solution ofpotassium hydroxide in water was heated for 3 hours at 100. The solutionthus obtained was di- .uted with water, cooled in an ice water bath, andacidiied with 2N hydrochloric acid. The precipitate which t'ormed wasfiltered and dried under vacuum. The solid )btained was crystallizedfrom methanol to give 75 mg. )f1,2-dihydro-3(4H),S-dibenzofurandicarboxylic acid, n.p. 322323. Anadditional 130 mg. of product, n.p. 321322, was obtained from the motherliquors.

Analysis Calcd. for C H O (260.24):

Found: C, 64.39; H, 5.01.

EXAMPLE 26 20 Preparation of 8-cyano-3,4-dihydro-2(lH)-dibenzofurancarboxylic acid To a solution of 1.47 g. of potassiumt-butoxide in 1 1 25 n1. of dimethylsulfoxide stirred vigorously at room.emperature, was added 993 mg. of 4-oxyiminocy- :lohexanecarboxylicacid. After 20 minutes, the reacion mixture was treated with 754 mg. of4- luorobenzonitrile, stirred for 2 hours, diluted with 100 nl. ofsaturated sodium chloride solution and acidified vith acetic acid.Precipitate was removed by filtration, vashed with water and withpentane and dried to give 370 mg. of 4-(4-cyanophenoxyimino:yclohexanecarboxylic acid as a tan powder, m.p. .60161 dec. Thismaterial can be used in the suczeeding step without furtherpurification.

A solution of 570 mg. of 4-(4-cyanophenoxyimino) :yclohexanecarboxylicacid in 10 ml. of acetic acid satlrated with hydrogen chloride washeated on a steam- )ath for hours. The reaction mixture was cooled tolbout and the solid which formed was removed by iltration.Crystallization from tetrahydrofuran-ether gave 230 mg. of8-cyano-3,4-dihydro-2(1H)-diben- ;ofurancarboxy1ic acid as whitecrystals, m.p. !51251.5. Recrystallized from tetrahydrofuran- :ther aswhite crystals, 8-cyano-3,4-dihydro-2(1H)- libenzofurancarboxylic acidhad a melting point of !49.5250.5.

Analysis Calcd. for C H NQ, (241.26):

C, 69.70; H, 4.59; N, 5.80.

Found: C, 69.85; H, 4.72; N, 5.81.

EXAMPLE 27 Preparation of 8-acetyl- 1 ,2-dihydro-3-( 4H)-dibenzofurancarboxy1ic acid uble inorganic material which formed wasremoved by filtration, and the filtrate was evaporated to dryness. Theresidue was crystallized from methanol-ether to give 2.1 g. of 3-(4-acetylphenoxyimino cyclohexanecarboxylic acid as light brown crystals,m.p. l67168.5 dec. A solution of 1.9 g. of this material in 25 ml. ofacetic acid saturated with hydrogen chloride was heated on a steambathfor 15 hours. The reaction mixture was cooled to about 25, and the solidwhich formed was removed by filtration. Crystallization fromtetrahydrofuran-ether gave 522 mg. of 8- acetyl- 1 ,2-dihydro-3-( 4H)-dibenzofurancarboxy1ic acid as grayish crystals, m.p. 234235.Recrystallized from tetrahydrofuran-ether as white crystals, S-acetyl-1,2-dihydro-3-(4H)-dibenzofurancarboxylic acid had a melting point of234-235.

Analysis Calcd. for C, H O (258.28):

Found: C, 69.72; H, 5.61.

EXAMPLE 28 Preparation of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3- carboxylic acid ethyl ester Asolution of 59 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethylester in 250 ml. of ethanol was added at reflux temperature over aone-hour period to a stirred solution of 34 g. of 4-chlorobenzenethioland 15.2 g. of potassium hydroxide in 750 ml. of ethanol. The reactionmixture was heated for another hour, cooled and filtered. The filtratewas evaporated, and the residue partitioned between ether and water. Theether layer was dried, evaporated, and the residue g.) was distilled togive 55 g. of 3-(4-chlorophenylthio)-4-oxo-cyclohexanecarboxylic acidethyl ester as a light yellow oil, b.p. 190/().O4 mm. The prod uctsolidified on standing, pale yellow crystals, m.p. 6372. The mixture of25 g. of this material and 375 g. of polyphosphoric acid was stirred at-85 for 3 hours, decomposed with ice and water, and extracted withether. The ether solution was washed successively with saturated sodiumbicarbonate solution and water, dried with sodium sulfate, andevaporated to give 23 g. of 8-chloro-l ,2,3,4-tetrahydrodibenzothiophene-3- carboxylic acid ethyl ester, yellow oilwhich gradually crystallized, m.p. 6()66. This material may be used inthe next step without further purification. Recrystallized from hexaneas white crystals, 8-chloro-l,2,3,4-tetrahydrodibenzothiophene-3-carboxylic acid ethyl ester had a meltingpoint of 7577.

Analysis Calcd. for C, F,H, F,CIO S (294.80):

Found: C, 61.14; H, 5.13.

EXAMPLE 29 Preparation of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3- carboxylic acid A solution of 22.8g. of 8'chloro 1,2,3,4- tetrahydrodibenzothiophene-3-carboxylic acidethyl ester, 320 ml. of 1N sodium hydroxide, and 640 ml. of ethanol werestirred at reflux temperature for 5 hours and then concentrated to asmall volume. The residue was mixed with 0.5 liter of water, charcoal,and thereafter filtered. The filtrate was cooled while adding 50 ml. ofconcentrated hydrochloric acid. The resultant precipitate was removed byfiltration and dried to give 19.1 g. of a solid, m.p. 222 -229.Crystallization from acetone-ether gave 10.75 g. of 8-chloro-1,2,3,4-tetrahydrodibenzothiophene-3 carboxylic acid as yellow crystals, m.p.22823l.

Analysis Calcd. for C H ClO S (266.74):

Found: C, 58.65; H, 4.31.

EXAMPLE 30 Preparation of l ,2-dihydro-3-(4H),8-dibenzofurandicarboxylic acid diethyl ester A solution of 226 mg. ofl,2-dihydro-3-(4H),8- dibenzofurandicarboxylic acid in 50 ml. of ethanolsaturated with hydrogen chloride was heated at reflux temperature for 1hour while continuing introduction of hydrogen chloride. Gasintroduction was terminated, and the solution was boiled for anadditional 2 hours and then evaporated. The oily residue was dissolvedin 75 ml. of methylene chloride and the solution was washed with one 25ml. portion of 1N sodium hydroxide and two 25 ml. portions of water. Theaqueous layers were extracted with two 50 ml. portions of methylenechloride. The organic layers were combined, dried with anhydrous sodiumsulfate and evaporated to dryness to give 247 mg. of oil whichcrystallized, m.p. 58-6 1. Recrystallization from ether-pentane afforded179 mg. of l,2-dihydro-3-(4l-l),8-dibenzofurandicarboxylic acid diethylester, m.p. 6363.5.

Analysis Calcd. for: C I-L O (316.34):

C, 68.34; H, 6.37. H

Found: C, 68.49; H, 6.54.

EXAMPLE 31 Preparation of 7-chloro-1 ,2-dihydro-3-( 4H)-dibenzofurancarboxylic acid Z-dimethylaminoethyl ester hydrochloride Amixture of 251 mg. of 7-chloro 1,2-dihydro- 3(4H)-dibenzofurancarboxylicacid, 304 mg. of anhydrous potassium carbonate and 25 ml. ofdimethylformamide was stirred at room temperature for 0.75 hour. Asolution of 173 mg. of 2-dimethylaminoethyl chloride hydrochloride in 5ml. of dimethylformamide was then added and the mixture was stirred for16 hours, heated at reflux temperature for one hour and evaporated. Theresidue was dissolved in 100 ml. of methylene chloride and washed withthree 50 ml. portions of water. The aqueous layers were extracted withtwo 100 ml. portions of methylene chloride. The organic layers werecombined, dried with anhydrous sodium sulfate and evaporated. A solutionof the residual oil in methanol was acidified with methanolic hydrogenchloride and evaporated. Crystallization of the residue from methylenechloride-ether containing a little methanol yeilded 174 ing. of7-chloro-l.2-dihydro-3(4H)- dibenzofurancarboxylic acid2-dimethylaminoethyl esterhydrochloride, m.p., 178.5 181.

Analysis Calcd. for: C H CINO 'HCI (358.27):

C. 56.99; H, 5.91; N, 3.91.

Found: C, 56.74; H, 5.89; N, 3.87.

EXAMPLE 32 Preparation of i2,3-dihydro-7-nitro-1H-cyclopenta[b]benzofuran-lcarboxylic acid and l,3-dihydro-7-nitro-2H-cyclopenta[b]benzofuran-2- carboxylic acid Amixture of 5.5 g. of potassium t-butoxide and 3.5 g. of3-oxyiminocyclopentanecarboxylic acid in 45 ml. of dimethylsulfoxide wastreated with 2.6 ml. of 4- fluoronitrobenzene, stirred at roomtemperature for 1.5 hours, diluted with 475 ml. of saturated sodiumchloride solution and acidified with acetic acid. The precipitate whichformed was removed by filtration, washed successively with water andpentane, dried and crystallized from tetrahydrofuran-ether-pentane togive 81 1 mg. ofyellow crystals, m.p. 141 .5-l42.5. 291 mg. of theproduct so obtained was treated with 3.5 ml. of a saturated solution ofhydrogen chloride in acetic acid, and the mixture was stirred for 17hours at room temperature. The solid was removed by filtration, washedwith acetic acid and dried to give 201 mg. of white crystals, m.p.203-205 (dec). The product was shown by NMR spectra to contain a 7:3ratio of 2,3-dihydro-7- nitro- 1 H-cyclopenta[ b]benzofuran- 1carboxylic acid and l,3-dihydro-7-nitro-2H-cyclopenta[ b]benzofuran-2-carboxylic acid.

2,3-Dihydro-7-nitro-lH-cyclopenta[b]benzofuran-1- carboxylic acid or 1,3-dihydro-7-nitro-2H- cyclopenta[b]benzofuranQ-carboxylic acid can beconverted to 2,3-dihydro-7-amino-l H-cyclopenta[b]benzofuran-1-carboxylic acid or 1,3-dihydro-7-amino-2H-cyclopenta[b]benzofuran-2- carboxylic acid,respectively, utilizing known procedures, for example, by chemicalreduction, for instance, with iron and hydrochloric acid, or bycatalytic reduction employing a catalyst, such as Raney nickel and thelike.

2,3-Dihydro-7aminol H-cyclopenta[b]benzofuranl-carboxylic acid or1,3-dihydro-7-amino-2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to 2,3-dihydro7acylamido- 1 H-cyclopenta[b]benzofuran-l-carboxylic acid or 1,3-dihydro-7-acylamido-2l-l-cyclopenta[b]benzofuran-2- carboxylic acid,respectively, utilizing known procedures, for example, acylation with anacylating agent, such as acyl halide or an acyl anhydride.

2,3-Dihydro-7-aminol H-cyclopenta[b]benzofuran- 1 -carboxylic acid or1,3-dihydro-7-amino2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to 2,3-dihydro-7-mono-lower alkylamino-1H-cyclopenta[b]benzofuran-1-carboxylic acid (or 2,-S-dihydro-7-di-lower-alkylamino-1H- cyclopenta[b]benzofuranl -carboxylicacid) or 1 ,3-dihydro-7-mono-lower alkylamino-ZH-cyclopenta[b]benzofuran-2carboxyic acid (or 1,3-

dihydro-7-di-lower-alkylamino-2H- cyclopenta[b]benzofuran-2-carboxylicacid), respectively, utilizing known procedures, for example, utilizingan alkylating agent, such as an alkyl-halide.

2,3-Dihydro-7-amino- 1 H-cyclopenta[ b]benzofuranl-carboxylic acid or 1,3-dihydro-7-amino-2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to a diazonium salt utilizing known procedures, for example,by reaction with sodium nitrite and a mineral acid, such as hydrohalicacid. The diazonium group can then be replaced by halogen, cyano, hy-

rox lower alkoxy or hydrogen, utilizing known proedures iw example, bymixing a diazonium salt soluion with, lor example, a cuprous halide,cuprouscyaide, water, an alcohol or a reducing agent, such asypophosporic acid, respectively, at room temperature r occasionally atelevated temperature to obtain the orresponding 2,3-dihydro-7-halol H-yclopenta[b]benzofuran-l-carboxylic acid or 1,3- ihydro-7halo-2H-cyclopenta[b]benzofuran-2- arboxylic acid, respectively, or thecorresponding 2,3-ihydro-7-hydroxy-1H-cyclopenta[b]benzofuran-larboxylic acid orl,3-dihydro-7-hydroxy-2H- yclpenta[b]benzofuran-2-carboxylic acid,respeclvely, or the corresponding 2,3-dihydro-7-lower alkoxlH-cyclopenta[b]benzofuran l -carboxylic acid or ,3-dihydro-7-loweralkoxyl-2H- yclopenta[b]benzofuran-2-carboxylic acid, respec ively, orthe corresponding 2,3 dihydroli-lyclopenta[ b]benzofuranl -carboxylicacid or ,3-dihydro-2H-cyclopenta[9 benzofuran-Z-carboxylacidrespectively.

EXAMPLE 33 Preparation of -(4-cyanophenoxyimino)cyclopentanecarboxylicacid Amixture of 5.5 g. of potassium t-butoxide and 3.65 of3-oxyiminocyclopentanecarboxylic acid in 40 ml. f dimethylsulfoxide wastreated with 2.96 g. of 4- luorobenzonitrile, stirred at roomtemperature for 3 lOUI'S, diluted with 400 ml. of saturated sodiumchloide solution and acidified with 25 ml. of acetic acid. heprecipitate which formed was removed by filtraion, washed successivelywith water and pentane, .ried and crystallized fromtetrahydrofuran-etherentane to give 2.5 g. of 3-(4-cyanophenoxyimino)cylopentanecarboxylic acid, tan crystals, m.p. 60.5l6l (dec.)

Analysis Calcd. for C H N O (244.24):

C, 63.92; H, 4.95; N, 11.47.

Found: C, 63.70; H, 5.02; N, 11.36.

EXAMPLE 34 Preparation of 7-cyano-2,3-dihydrol l l-cyclopentalb]benzofuranl carboxylic acid and 7-cyanol ,3dihydro-2H-cyclopenta[b]benzofuran-2- carboxylic acid A mixture of 1,06 g. of3-(4-cyanophenoxyimino)cy- :lopentanecarboxylic acid and ml. of asaturated soution of hydrogen chloride in acetic acid was stirred or 21hours at room temperature. The solid was renoved by filtration, washedwith hexaneacetic acid 2:1 and then with hexane and dried to give 1.05g. of tan powder, m.p. 2()6-208 (dec.). The product was hown by NMRspectra to be a mixture containing an vpproximately 1:1 ratio of7-cyano-2,3-dihydro-lH- yclopenta[b]benzofuran-l-carboxylic acid and 7-yano-l ,3-dihydro-2H-cyclopenta[b]benzofuran-Z- arboxylic acid.

7-Cyano-2,3-dihydrol H-cyclopenta[ b benzofuran- -carboxylic acid or7-cyanol ,3-dihydro-2H- yclopentalblbenzofuran-2-carboxylic acid can beonverted to 7-carboxy-2,3-dihydro-1H-yclopenta[blbenzofurznrl-carboxylic acid or 7 arboxyl.3-dihydro-2H-cyclopenta[ b]benzofuran-2- arboxylic acid, respectively,utilizing known procedures, for example, hydrolysis with acid ,or basein water or alcohol. I g

7-Cyano-2,3-dihydrol H-cycl0penta[ b]benzofuran- Iccarboxylic acid or7-cyano-l,3-dihydro-2H- cyclopenta[b]benzofuran-2-carboxylic acid can beconverted to the 7-amido-2,3-dihydro l H-cyclopenta[b]benzofuran-l-carboxylic acid or 7- amidol,3-dihydro-2H-cyclopenta[ b]ben7.ofuran-2- carboxylic acid,respectively, utilizing known procedures, for example, partialhydrolysis, in strong hydrochloric acid or polyphosphoric acid.

7-Cyano-2,3-dihydrol H-cyclopenta[blbenzofuranl-carboxylic acid or7cyanol ,3-dihydro2H- cyclopenta[b]benzofuran-Z-carboxylic acid can beconverted to a 7-l0wer alkanoyl2,3-dihydro-1H-cyclopenta[b]benz0furan-l-carboxylic acid or a 7- loweralkanoyl-l,3-dihydro-2H cyclopenta[b]benzofuran-Z-carboxylic acid,respectively, utilizing known procedures, for example, a Grignardreagent, such as a lower alkyl magnesium halide.

EXAMPLE 35 Capsule Formulation zofurancarboxylic acid is mixed with I25parts of lactose and 30 parts of corn starch in a suitable mixer.

2. The mixture is further blended by passing through a FitzpatrickComminuting Machine with a No. 1A screen with knives forward.

3. The blended powder is returned to the mixer, 5 parts talc are addedand blended thoroughly.

4. The mixture is filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine.

EXAMPLE 36 Tablet Formulation Per Tablet 8-Cyanol ,2-dihydro-3(4H)-dihcnzofuran carboxylic acid 25 mg Dicalcium Phosphate Dihydrate,Unmillcd mg Corn Starch 24 mg Magnesium Stearatc 1 mg Total Weight 225mg Procedure I. 25 Parts of 8-cyano-l,2-dihydro-3-(4-H)-dibenzofurancarboxylic acid and 24 parts of cornstarch are mixed together and passed through a No. ()0 screen in Model JFitzmill with hammers forward.

2. This premix is then mixed with 175 parts of dical cium phosphate andone-half of a part of the magnesium stearate, and passed through a No.1A screen in Model J Fitzmill with knives forward, and slugged.

EXAMPLE 37 Tablet Formulation Per Tablet S-Cyano-l .2-dihydro'3( 4Hdibenzofurancarboxylic acid 100 mg Lactose. U.S.P. 202 mg Corn Starch.U.S.P. 80 mg Amijel B011" 20 mg Calcium Stearatc 8 mg Total Weight 410mg A prehydrolyzed food grade corn starch. Any similar prehydrolyzedcorn starch may be used.

Procedure 1. 100 Parts of 8-cyano-1,2-dihydro-3-(4H)-dibenzofurancarboxylic acid, 202 parts of lactose, 80parts of corn starch. and 20 parts Amijel Boll are blended in a suitablemixer.

2. The mixture is granulated to a heavy paste with water and the moistmass is passed through a No. 12 screen. It is then dried overnight at100F.

3. The dried granules are passed through a No. 16

screen and transferred to a suitable mixer. The calcium stearate isadded and mixed until uniform.

4. The mixture is compressed at a tablet weight of 410 mg using tabletpunches having a diameter of approximately three-eighths inch. (Tabletsmay be either flat or biconvex and may be scored if desired).

EXAMPLE 38 Parenteral Formulation Each 1 cc ampul contains: Per cc8-Cyano- I .2-dihydro-3(4H )-dibcnzofuran- 10.2 mg

carhoxylic acid (2 7r excess) Methyl Parahcn. U.S.P. 1.8 mg PropylParabcn. U.S.P. 0.2 mg Sodium Hydroxide, U.S.P. q.s. ph 9.0 Water forInjection. U.S.P. q.s. ad cc dibenzofurancarboxylic acid is added underan atmosphere of nitrogen and stirred until completely dispersed.

3. The Sodium Hydroxide was added as a 10 percent solution until the pHwas adjusted to 9.0 plus or minus 0.1, and the drug is completelydissolved.

4. Sufficient Water for Injection is then added to make a total volumeof 10,000 cc.

5. This solution is then filtered through an 02 Selas can dle, filledinto suitable size ampuls, gassed with nitrogen and sealed. It isautoclaved at 10 lbs PS1 for 30 minutes.

EXAMPLE 39 Suppository Formulation Per 1.3 Gm Suppository8-Cyano-1,2-dihydro-3(4H)-dibenzofurancarboxylic acid 0.025 mg WecobeeM* 1.230 mg Camauba Wax 0.045 gm E. F. Drew Company 522 Fifth Avenue NewYork, New York Procedure 1. 123 Parts of Wecobee M and 4.5 parts ofcarnauba wax are melted in a suitable size glass-lined container(stainless steel may also be used), mixed will and cooled to 45C.

2. 2.5 Parts of 8-cyano-l ,2-dihydro-3(4H)-dibenzofurancarboxylic acid,which has been reduced to a fine powder with no lumps, is added andstirred until completely and uniformly dispersed.

3. The mixture is poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

4. The suppositories are cooled and removed from molds, and individuallywrapped in wax paper for packaging. (Foil may also be used.)

We claim: 1. A compound of the formula HAL C00 2 wherein R is loweralkyl, and HAL is halogen.

2. The compound in accordance with claim 1, 3-

bromo-4-ketocyclohexanecarboxylic acid ethyl ester.

1. A COMPOUND OF THE FORMULA
 2. The compound in accordance with claim 1,3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester.